- Main
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.
- Author(s): Schoof, Michael
- Faust, Bryan
- Saunders, Reuben A
- Sangwan, Smriti
- Rezelj, Veronica
- Hoppe, Nick
- Boone, Morgane
- Billesbølle, Christian B
- Puchades, Cristina
- Azumaya, Caleigh M
- Kratochvil, Huong T
- Zimanyi, Marcell
- Deshpande, Ishan
- Liang, Jiahao
- Dickinson, Sasha
- Nguyen, Henry C
- Chio, Cynthia M
- Merz, Gregory E
- Thompson, Michael C
- Diwanji, Devan
- Schaefer, Kaitlin
- Anand, Aditya A
- Dobzinski, Niv
- Zha, Beth Shoshana
- Simoneau, Camille R
- Leon, Kristoffer
- White, Kris M
- Chio, Un Seng
- Gupta, Meghna
- Jin, Mingliang
- Li, Fei
- Liu, Yanxin
- Zhang, Kaihua
- Bulkley, David
- Sun, Ming
- Smith, Amber M
- Rizo, Alexandrea N
- Moss, Frank
- Brilot, Axel F
- Pourmal, Sergei
- Trenker, Raphael
- Pospiech, Thomas
- Gupta, Sayan
- Barsi-Rhyne, Benjamin
- Belyy, Vladislav
- Barile-Hill, Andrew W
- Nock, Silke
- Liu, Yuwei
- Krogan, Nevan J
- Ralston, Corie Y
- Swaney, Danielle L
- García-Sastre, Adolfo
- Ott, Melanie
- Vignuzzi, Marco
- QCRG Structural Biology Consortium
- Walter, Peter
- Manglik, Aashish
- et al.
Published Web Location
https://doi.org/10.1126/science.abe3255Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.